Effects of selective and unselective endothelin-receptor antagonists on prostacyclin synthase gene expression in experimental pulmonary hypertension

Objective. Compared to the unselective endothelin (ET) receptor antagonist (Bosentan), superior effects of selective ET-A-receptor blockage (Ambrisentan) for the treatment of pulmonary hypertension (PH) are expected due to ET-B-receptor mediated beneficial effects. Our hypothesis was that treatment with Ambrisentan leads to an increase in prostacyclin synthase I (PGIS) expression compared to Bosentan. Material and methods. To test this hypothesis, rats were treated with either monocrotaline (MCT) only, MCT+Ambrisentan or MCT+Bosentan. After 4 weeks, right ventricular systolic pressure (RVSP), pulmonary vascular remodelling and right ventricular hypertrophy(RV/(LV+S)) were measured. Results. In MCT only treated animals, significantly greater expression of PGIS mRNA was found in the lungs compared to control animals, and this was confirmed by immunohistochemical analysis indicating increased staining of PGIS in the very small pulmonary arteries (17% greater expression of PGIS mRNA in MCT versus control, p=0.002; Remmele score (RS): 51 versus 102, p=0.009). Treatment with Bosentan resulted in a significantly lower expression of PGIS mRNA compared to Ambrisentan and MCT only (7% versus 18%, p=0.003 and 7% versus 17 %, p=0.004). This observation was also confirmed by immunohistochemical analysis (RS very small arteries: 45 versus 81, p=0.003; RS small arteries: 45 versus 108, p=0.014). No difference was observed in RVSP, RV/(LV+S) or pulmonary vascular remodelling between the two treatment groups (RVSP: 28 versus 39 mmHg, p=0.189; RV/( LV+S) 0.46 versus 0.48, p=0.818; medial area: 78.3% versus 75.2%, p=0.823). Conclusions. Treatment with Bosentan leads to lower PGIS expression in pulmonary arteries compared to Ambrisentan, although the greater PGIS expression by Ambrisentan treatment had no benefical effect on pulmonary haemodynamics.